Decoding Neurodegeneration: A Comprehensive Review of Molecular Mechanisms, Genetic Influences, and Therapeutic Innovations
<p>The proposed model depicts various potential molecular mechanisms responsible for the disturbed copper homeostasis observed in hepatocytes expressing Wilson’s disease ATPase mutations. Under normal circumstances, this ATPase normally resides in the trans-Golgi network, but when exposed to high copper levels, it relocates into a vesicular compartment of its cell’s cytoplasm, where it accumulates copper before returning to its trans-Golgi network and eventually excreting copper into its bile.</p> "> Figure 2
<p>NPC1 disease is a neurodegenerative disorder caused by genetic mutations of the lysosomal cholesterol transporter NPC1. Cholesterol accumulates in these organelles and begins its pathological process, ultimately resulting in greater excitability of neurons affected.</p> "> Figure 3
<p>This diagram depicts the complex cellular model of Tay–Sachs disease. After alpha subunit undergoes glycosylation into the ER and structural stabilization from calreticulin/calnexin cycle, it can properly fold, forming the beta subunit, and both will be exported to the Golgi. If alpha subunit undergoes improper folding, glycans are removed before proteasomal degradation. A possibility to avoid this issue is Kifunensine, an inhibitor for ER Manosidase I trimming of glycans.</p> ">
Abstract
:1. Frontotemporal Demetia (FTD)
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- PiD (Pick’s disease) typically presents as behavioral variant frontotemporal dementia (bvFTD) or nonfluent variant primary progressive aphasia (nfvPPA), with motor deficits being rare. Histological characteristics of PiD include neuronal loss and swelling known as Pick cells; distinct large spherical neuronal cytoplasmic inclusions called Pick bodies may also be observed in some individuals with the disorder [14].
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- Progressive supranuclear palsy (PSP) typically presents as a movement disturbance characterized by early postural instability, axial rigidity, bradykinesia, and ophthalmoplegia. Cognitive impairment may be mild; however, some cases with PSP pathology show dementia similar to bvFTD or nfvPPA. PSP pathology also involves degeneration in multiple subcortical regions, including the striatum, globus pallidus, subthalamic nucleus, midbrain, tectum/tegmentum, substantia nigra, basis, pontis, cerebellar dentate nucleus, and cerebellar peduncles [15].
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- Patients diagnosed with corticobasal degeneration (CBD) often display corticobasal syndrome (CBS), characterized by bradykinesia, rigidity, dystonia, apraxia, cortical sensory signs, alien limb phenomenon, and bradykinesia [16].
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- They may also show features of FTD (bvFTD or nfvPPA), displaying depigmentation in the substantia nigra, atrophy of globus pallidus, as well as focal and asymmetric cerebral cortical atrophy—histopathological features that overlap between PSP and CBD such as tau-immunoreactive glial cells as well as NCI histopathological features of both syndromes [17].
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- FTD caused by mutations of the MAPT gene is an autosomal dominant form linked to chromosome 17 (FTDP-17T) that accounts for roughly 10% of familial FTD cases. MAPT pathogenic mutations include missense or deletions in exons 1 and 9–13 or mutations after exon 10 that mainly manifest themselves through behavior changes, personality shifts, cognitive dysfunction, and atypical Parkinsonism, typically seen through behavior and personality alterations, cognitive deficits, and Parkinsonian-like symptoms as well as neuropathology featuring hyperphosphorylated tau deposits within gray and white matter structures [18].
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- Mutations to the VCP gene (valosin-containing protein) cause a rare familial syndrome known as inclusion body myopathy, Paget’s disease of bone, and FTD with variable penetrance (IBMFD). VCP belongs to the AAA-ATPase gene superfamily and serves as a molecular chaperone involved in various cellular activities that are either directly or indirectly controlled by UPS (ubiquitin–proteasome system) [19].
2. Spinocerebellar Ataxias (SCA)
3. Lewy Body Dementia (DLB)
Treatment/Drug | Key Details and Outcomes | Citation |
---|---|---|
Rivastigmine |
| [65,66] |
Galantamine |
| [66,68] |
Memantine |
| [67] |
Levodopa |
| [68] |
Zonisamide |
| [69] |
4. Friedreich’s Ataxia (FA)
5. Progressive Supranuclear Palsy (PSP)
6. Corticobasal Degeneration (CBD)
7. Wilson’s Disease
8. Niemann–Pick Disease
- -
- Lessening the volume of intra-lysosomal free cholesterol;
- -
- Curbing the production of glucosylceramide by inhibiting its synthase;
- -
- Regulating inflammatory reactions and immune responses;
- -
- Augmenting the transfer of free cholesterol from the lysosomal section into the cytosol;
- -
- Modulating the expression of genes vital for initiating cell differentiation by hindering histone deacetylases (HDAC);
- -
- Employing pharmacological chaperones to promote cellular protein repair pathways via the activation of molecular chaperones, like heat shock proteins;
- -
- Exploring the potential of gene therapy.
9. Tay–Sachs Disease
10. Fahr’s Syndrome
11. Conclusions and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Study Focus | Key Findings and Techniques | Citation |
---|---|---|
Origin and employment of iPSCs | Derived from somatic cells like fibroblasts. Uses agents Oct4, Klf4, Sox2, and c-Myc. | [22] |
iPSC models for FTLD-tau | Focuses on fibroblasts from MAPT alterations. | [25] |
Patient-sourced iPSCs with 10 + 16 mutation | Noted surge in 4R tau expression, leading to increased 4R:3R tau isoform ratio. | [26] |
Tau pathology in N279K iPSC-derived neurons | Observed shifts in 4R:3R tau isoform balance, with increased 4R tau levels. | [27] |
iPSCs from patients with N279K mutation | Differentiated into NPCs. Used CRISPR/Cas9 for isogenic controls. Differentiated into astrocytes using Sox10 and growth factors. | [27] |
Molecular Target | Pathway | SCA Subtype | Possible Medication |
---|---|---|---|
PP2 | PP2 | 1, 12 | PP2-mediated regulators |
PRKC | PRCK | 1, 14 | PRKC-mediated regulators |
Gene transcriptors | Multiple | 1–3, 6, 7 | HDACis |
Aggregation | Autophagy Transglutaminase | 1–3, 6, 7, 17, DRLPA | Rapamycin Cystamine |
Chaperons | HSR, UPR | 1–3, 6, 7, 17, DRLPA | Arimoclomol |
Ubiquitin | UPS | 1–3, 6, 7, 17, DRLPA | UPS derivates |
Mitochondrial approach | Multiple | Any | Coenzyme Q10 |
Calcium activity | Calcium mechanisms | 1, 6 | Ca2+ blockers |
Dopamine pathway | Dopamine | 1–3, 6, 17, 27 | Levodopa, anticholinergic, and dopaminergic pharmaceutical therapies |
Neurotransmitters | GABA | Any | Glutamate inhibitors |
Ataxins | RNAi | Any | RNAi |
Caspases | Caspases | Any | Cystamine |
Treatment/Research Focus | Research Focus | Citation |
---|---|---|
AAV vector method targeting ATXN1 | Introducing AAV vectors with shRNA targeting ATXN1 led to reduced mutant ATXN1 expression. This improved motor function and normalized Purkinje cells. Research now focuses on specifically targeting mutant alleles in polyQ disorders, including SCA3. | [42,43] |
Research on polyQ expansion in SCA17 | PolyQ expansion in TBP affects its DNA binding and interactions with transcription regulators. This might reduce the expression of specific genes, impacting neuronal function. However, the majority of genes remain unaffected. | [44] |
Treatment/Drug | Key Details and Outcomes | Citation |
---|---|---|
Levodopa with carbidopa or benserazide |
| [96] |
Donepezil |
| [97] |
Amitriptyline |
| [98] |
Amantadine |
| [98] |
Carbidopa-levodopa |
| [98] |
Treatment/Drug | Application/Condition | Key Outcomes | Citation |
---|---|---|---|
Dopaminergic treatments, benzodiazepines, anticholinergics | Parkinsonism | Typically ineffective and might lead to side effects such as cognitive decline. | [98] |
Levodopa | Parkinsonism in CBD/CBS | Minimal effects, with some reports indicating brief mild to moderate improvement. | [101] |
Botulinum toxin injections | Dystonia in CBS | Effective for pain relief, enhancing hygiene, countering secondary contractures, and occasionally improving limb functionality in early disease stages. | [108] |
Benzodiazepines (e.g., Clonazepam), anticholinergic drugs, muscle relaxants | Dystonia | Oral medications like these are often tried but seldom prove effective. | [109] |
Clonazepam | Myoclonus | Shows a favorable response, especially effective. | [109] |
Levetiracetam, gabapentin, valproic acid | Myoclonus | Can be beneficial, with some accounts of use. | [109] |
Model/Component | Description/Effect | Citation |
---|---|---|
R778L mutation model | Differentiated into hepatocyte-like cells (HLCs) | [143] |
HLCs with R778L mutation | Showed heightened susceptibility to excessive copper, more sensitive to copper-induced cytotoxicity | [143] |
Treatment/Therapeutical Approaches | Description/Effect | Citations |
---|---|---|
Cholesterol-lowering drugs | Not effective in altering disease trajectory | [154] |
Regulating inflammatory reactions | [154] | |
Curbing glucosylceramide production | By inhibiting its synthase | [155] |
Augmenting free cholesterol transfer | Stimulating the transfer from lysosomal section into the cytosol | [155] |
Modulating gene expression | By hindering histone deacetylases (HDAC) | [155] |
Pharmacological chaperones | Promote cellular protein repair pathways via activation of molecular chaperones like heat shock proteins | [155] |
HP-β-CD | Cyclic oligosaccharide; limited by inability to penetrate blood–brain barrier | [154] |
Arimoclomol | Enhances heat shock protein gene expression, aiding cellular protective mechanisms | [155] |
Miglustat | Sole officially approved treatment in EU for neurological symptoms; may slow or mitigate disease progression | [157] |
General Medications | Manage Symptoms: Anxiety, Depression, OCD, Dystonia | Citations |
---|---|---|
Oxybutynin | Treat urinary incontinence | [181] |
Antiepileptics | Address seizures | |
Phosphate and calcium level regulation | Address seizures and movement disorders, especially those linked to parathyroid imbalances | |
Alpha hydroxy vitamin D3 + corticosteroids | Reversed some neurological deficits | |
Clonazepam and atypical antipsychotics | Provide therapeutic benefits | |
Lithium | Prescribed with caution due to increased seizure risk | |
Carbamazepine, benzipenes, barbiturates | Might intensify gait disturbances | |
Antidepressants and anxiolytics | Prescribed with caution due to potential side effects at lower thresholds in Fahr’s syndrome patients | |
iPSC models (SLC20A2 mutations) | Research tool for studying Fahr’s disease mechanisms, potential for drug- and gene-based intervention studies | [182] |
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Voicu, V.; Tataru, C.P.; Toader, C.; Covache-Busuioc, R.-A.; Glavan, L.A.; Bratu, B.-G.; Costin, H.P.; Corlatescu, A.D.; Ciurea, A.V. Decoding Neurodegeneration: A Comprehensive Review of Molecular Mechanisms, Genetic Influences, and Therapeutic Innovations. Int. J. Mol. Sci. 2023, 24, 13006. https://doi.org/10.3390/ijms241613006
Voicu V, Tataru CP, Toader C, Covache-Busuioc R-A, Glavan LA, Bratu B-G, Costin HP, Corlatescu AD, Ciurea AV. Decoding Neurodegeneration: A Comprehensive Review of Molecular Mechanisms, Genetic Influences, and Therapeutic Innovations. International Journal of Molecular Sciences. 2023; 24(16):13006. https://doi.org/10.3390/ijms241613006
Chicago/Turabian StyleVoicu, Victor, Calin Petre Tataru, Corneliu Toader, Razvan-Adrian Covache-Busuioc, Luca Andrei Glavan, Bogdan-Gabriel Bratu, Horia Petre Costin, Antonio Daniel Corlatescu, and Alexandru Vlad Ciurea. 2023. "Decoding Neurodegeneration: A Comprehensive Review of Molecular Mechanisms, Genetic Influences, and Therapeutic Innovations" International Journal of Molecular Sciences 24, no. 16: 13006. https://doi.org/10.3390/ijms241613006